Multifunctional nanoparticles (NPs) that enable diagnostic imaging and therapeutic drug delivery are rapidly emerging as a powerful platform for cancer therapy. The ability to monitor drug delivery non-invasively in situ will provide clinicians with an unprecedented tool that may facilitate personalized therapeutic regimens for each patient's tumor. Additionally, NPs are attractive as drug delivery vehicles because they can deliver potent doses of therapeutic agents to cancer cells with significantly improved specificity and reduced toxicities. These advantages are achieved through targeted delivery and release of chemotherapeutics specifically in tumor cells. Furthermore, NPs can be engineered to bypass biological barriers such as the blood-brain barrier (BBB), which normally prevents the passage of more than 98% of drugs to the brain and achieve desirable biodistribution profiles that minimize chemotherapy side effects. Proper integration of these favorable attributes in a single nanoparticle formulation is expected to offer a solution for highly intractable cancers such as glioblastoma multiforme (GBM).
GBMs are malignant brain tumors that are among the most lethal cancers, striking 14,000 individuals in the U.S. each year. Therapy has long included surgery followed by conformal radiotherapy. Recent clinical trials have documented that inclusion of the DNA methylating agent temozolomide (TMZ) in the post-operative therapy of newly diagnosed GBMs has produced the first significant improvement in survival in the last 30 years. The clinical efficacy of TMZ reflects, in part, its ability to cross the BBB. Clinical outcome, however, is not improved by TMZ in the majority of GBMs because of resistance mediated in large part by O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein that removes the cytotoxic O6-methylguanine lesions produced by TMZ.
In vitro studies suggest that GBM resistance to TMZ can be overcome by ablating MGMT activity with DNA repair inhibitors such as O6-benzylguanine (BG). BG serves as a pseudo-substrate for MGMT and irreversibly inactivates the DNA repair protein. However, clinical trials have shown that inclusion of BG in TMZ treatment regimens reduces the maximum tolerated dose (MTD) of TMZ by 50%. The significant reduction in MTD is primarily caused by the poor pharmacokinetics of BG; BG poorly permeates across the BBB, is limited by a short blood half-life, and rapidly accumulates in clearance organs and bone marrow producing significant myelosuppression in combination with TMZ. Hence, prognosis remains dismal with only 2% of patients surviving 5 years. This necessitates the development of novel therapeutic agents that can circumvent resistance mediated by tumor biology (e.g., drug resistance due to DNA repair) and by normal physicological barriers (e.g., BBB).
Despite the advances in the treatment of GBM noted above and in view of the GBM resistance to TMZ, a need exists for effective compositions and methods for treating GBM. The present invention seeks to fulfill this need and provides further related advantages.